Spotlight on the FDA

Biosimilars, Guidelines for Clinical Studies, and New Policies on cGMP Inspections and Reference-Listed Drug Choice

FDA’s RLD Choice Policy and Change Prohibition: A New Tool in the Lifecycle Management Toolbox

Kurt R. Karst

On November 25, 2008, the FDA granted a citizen petition submitted by Osmotica Pharmaceutical requesting that FDA determine that any company with a pending ANDA for a proposed venlafaxine HCl extended-release tablet drug product be required to submit a new ANDA to FDA citing Osmotica’s approved venlafaxine HCl extended-release tablets drug product as the reference listed drug (RLD). The company also asked that FDA require any such ANDA applicant to conduct new bioequivalence studies comparing its proposed drug product to Osmotica’s approved drug product.

FDA’s petition decision: (1) affirms the agency’s longstanding RLD Change Policy, which requires a generic applicant with a pending ANDA subject to an approved suitability petition to change RLD and provide appropriate bioequivalence information once the agency approves an application for the drug product covered by the suitability petition; (2) affirms FDA’s RLD Choice Policy, under which a generic applicant must choose the most pharmaceutically equivalent listed drug as the RLD; and (3) implements FDC Act §505(j)(2)(D)(i), which was added to the statute in 2003 by the Medicare Prescription Drug, Improvement, and Modernization Act (MMA) and precludes an applicant with a pending ANDA from amending that application to change RLD.

Under FDA’s RLD Choice Policy, a generic applicant should refer to the approved pharmaceutical equivalent designated by FDA as the RLD as its basis for ANDA submission. As FDA explained in its RLD Choice Petition Response:

“if a tablet and a capsule are approved for the same moiety with patents listed for the tablet and none listed for the capsule, an ANDA applicant seeking approval for a tablet should cite the approved tablet as the [RLD]. It should not circumvent the patents on the tablet by citing the capsule as the [RLD] and filing a suitability petition under [FDC Act § 505(j)(2)(C)] and 21 CFR 314.93 seeking to change to a tablet dosage form.

Under FDA’s longstanding RLD Change Policy, the agency has required a generic applicant with a pending ANDA subject to an approved suitability petition to change RLD and provide appropriate bioequivalence information once the agency approved an application for the drug product covered by the suitability petition. For example, after FDA approved NDAs for carboplatin injection drug products that were also the subject of pending ANDAs submitted pursuant to an approved suitability petition, the agency required generic applicants to change RLD.

FDA has also required generic applicants to take the same action in an Rx-to-OTC switch scenario, where the agency approved a new NDA for an OTC drug product, thus creating a new RLD listed in the Orange Book that generic applicants must cite.

FDA’s RLD Change Policy became particularly important with the enactment of the MMA in 2003. The MMA amended the FDC Act to add §505(j)(2)(D)(i), which states: “[a]n applicant may not amend or supplement an [ANDA] to seek approval of a drug referring to a different listed drug from the listed drug identified in the application as submitted to [FDA].”

A similar provision was added to FDC Act §505(b)(4)(A) with respect to 505(b)(2) applications. That provision states: “[a]n applicant may not amend or supplement [a 505(b)(2) application] to seek approval of a drug that is a different drug than the drug identified in the application as submitted to [FDA].” Thus, given FDA’s RLD Change and Choice Policies, a generic applicant must cite the most appropriate RLD, and must change RLD (for a pending application) when a pharmaceutically equivalent listed drug is approved.

The MMA, however, precludes an ANDA applicant (and a 505(b)(2) applicant) with a pending application from changing RLD. Instead, Osmotica argued in its citizen petition that a new application must be submitted citing the appropriate RLD, and such application must contain the required bioequivalence data comparing the proposed generic drug to the new RLD (in this case, Osmotica’s approved venlafaxine HCl extended-release tablets drug product).

FDA concluded in its November 2008 petition response that:

“our requirement that an applicant with a pending ANDA subject to an approved suitability petition change the RLD upon FDA approval of an NDA for the same drug product described in the approved suitability petition reflects the Agency’s judgment that considerations regarding an ANDA’s limited reliance on an approved suitability petition are outweighed by the need for a clear determination of therapeutic equivalence for a generic drug product and protection of intellectual property rights accorded an NDA holder

“this approach reduces the potentially confusing proliferation of pharmaceutically equivalent drug products that have not demonstrated therapeutic equivalence, and ensures that ANDAs for venlafaxine HCl extended-release tablets will be therapeutically equivalent and thus substitutable for the RLD, Osmotica’s venlafaxine HCl extended-release tablets”

“FDA’s policy of requiring all pending ANDA applicants to change their basis for ANDA submission upon approval of an NDA for the same drug product described in the suitability petition is intended to ensure that ANDA applicants do not circumvent the patent certification requirements of section 505(j)(2)(A)(vii)-(viii) of the Act through the suitability petition process. In addition, our policy would appropriately protect any marketing exclusivity that has been granted to the newly approved RLD.”

“an ANDA for venlafaxine HCl extended-release tablets submitted based upon an approved suitability petition that was pending at the time of approval of Osmotica’s NDA 22-104 and that seeks approval for a pharmaceutically equivalent drug product must be withdrawn, as the ANDA is required to reference the corresponding approved strengths of Osmotica’s venlafaxine HCl extended-release tablets as its RLD, and section 505(j)(2)(D)(i) of the Act precludes such a change from being submitted as an amendment to an ANDA. If Sun or any other applicant wishes to pursue approval of an ANDA for venlafaxine HCl extended-release tablets, it must submit a new ANDA containing data and information required by section 505(j) of the Act for approval (including, but not limited to, a demonstration of bioequivalence to the RLD, Osmotica’s venlafaxine HCl extended-release tablets).”

“We note that our interpretation of § 505(b)(4)(A) of the Act, also added by the MMA, for 505(b)(2) applications is influenced by and intended to be consistent with section 505(j)(2)(D)(i) regarding ANDAs. Accordingly, a 505(b)(2) applicant may not amend or supplement a 505(b)(2) application to seek approval of a drug that relies on the Agency’s finding of safety and/or effectiveness for a drug that is different from the drug identified in a previous submission of the application.”

Thus, if at any time before approval of an ANDA (subject to an approved suitability petition) or a 505(b)(2) application, another drug product is approved that is the pharmaceutical equivalent—or that is more pharmaceutically similar to the product in a pending 505(b)(2) application—FDA could, as a result of the agency’s RLD choice policy, require the applicant to cite a new RLD, and, as a result of the statutory prohibition on amending an application to change RLD, FDA could require the applicant to submit a new application containing a certification or statement to any relevant Orange Book-listed patents (as well as required bioequivalence/bioavailability information).

The importance of FDA’s citizen petition response cannot be overstated. It has significant implications—and creates significant risk—for generic companies that rely on the suitability petition process. For 505(b)(2) applicants, it also creates a risk of application resubmission and underscores the importance of carefully choosing the appropriate listed drug(s) and creates a new lifecycle management tool for innovator companies.

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